Several lines of pharmacological and genetic evidence support the role of Melanin Concentrating Hormone Receptor-1 (hereafter “MCHR1”) as a modulator of food intake and body weight. Central administration of MCH increases food intake and body weight in both rats and mice. Chronic ICV infusion of MCH causes increased food intake and ultimately obesity in mice, while infusion of an MCH peptide antagonist blocks MCH-induced food intake and results in weight loss and decreased feeding in diet-induced obese mice.
The expression of both the MCH peptide and receptor are modulated by nutritional status. MCH mRNA is upregulated both in hyperphagic obese mice (ob/ob), and fasted animals. Targeted disruption of the gene for MCH peptide results in hypophagia and leanness. Disruption of the MCHR1 gene causes leanness, altered metabolism, and hyperlocomotion accompanied by mild hyperphagia. Conversely, over-expression of MCH peptide results in hyperphagia, obesity and diabetes. Small molecule MCHR1 antagonists have been shown to cause weight loss in rodent weight and feeding models after both oral and intraperitoneal administration; Eur. J. Pharmacol., 438:129-135 (2002), Nat. Med., 8:825-830 (2002), Eur. J. Pharmacol., 497:41-47 (2004).
MCHR1 has also been reported to play a key role in the pathogenesis of acute experimental colitis and possibly human TBD (inflammatory bowel disease). It has been shown that immunoneutralization is an effective treatment for TNBS-induced colitis. Kokkotou, E. et al., “Melanin-concentrating hormone as a mediator of intestinal inflammation”, PNAS, 105(30):10613-10618 (Jul. 29, 2008).
In addition, MCH and MCHR1 has also been reported to play a role in the endocrine and behavioral responses to stress. Treatment of rats and mice with MCHR antagonists produce a robust anti-depressant and anti-anxiolytic effect. (JPET DOI:10.1124/jpet.108.143362)
Small molecule MCHR1 antagonists have been reported in the literature. See, for example, United States Patent Application Publication No. US 2009/0011994, which discloses compounds having the following Formula:
wherein
is a phenylene ring or a heteroaryl ring which is a monocyclic ring or a bicyclic ring which contains one or two nitrogen atoms or one oxygen atom;
R1 is Z—Y—X—, wherein                X is O, S,        
                X is O, S,        Y is a bond, a 3- to 6-membered cycloalkyl, or an alkyl chain; and        Z is aryl such as phenyl and naphthyl, or heteroaryl such as pyridinyl, pyridimidinyl, pyrazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, or other “heteroaryl”; R2 is -E-G-(J)m, with m being an integer from 1 to 3;        
E is O, S, or a bond; G is lower alkyl, phenylalkyl, cycloalkyl, cycloalkylalkyl, alkylcycloalkyl, cycloalkoxy, alkylcycloalkoxy, or cycloalkoxyalkyl;
each J is independently hydrogen, hydroxyl, CN, —SO2R7, —SR7, —SOR7, lower alkyl, lower alkoxy, CF3, CF3O—, —COOR5 (wherein R5 is H, C1-3 alkyl, or cycloalkyl), or —CO—NR5aR6 wherein R5a and R6 are each independently selected from H, C1-3 alkyl, or cycloalkyl, or R5a and R6 taken together can be propanediyl, butanediyl or pentanediyl to form with the N atom to which they are attached a 4-, 5- or 6-membered cyclic amine, such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl, optionally substituted with substituents as set out for “heterocyclo”;
R7 is lower alkyl;
R3 is C1-6 alkyl, cycloalkyl, C1-6 alkoxy, halogen, hydrogen, —S—C1-6 alkyl, CN, CF3O, or CF3;
and wherein R2 and R3 can be taken together to form a 5- to 7-membered ring which is saturated, unsaturated, or partially unsaturated and may include an E heteroatom, which is O, or 0, 1 or 2 N atoms, which ring is substituted with one or two of —O-G-(J)m groups, wherein at least one J is OH, and optionally other substituents as set out for “alkyl”, “aryl”, or “heteroaryl”, such as alkyl and/or OH;
with the proviso that where
is a phenylene ring, E-G and R3 are not identical unsubstituted lower alkoxy groups, and when G is lower alkyl and J is H, R3 is not hydrogen; and
R8 and R9 are each independently hydrogen, halogen, or lower alkyl;
including esters thereof, prodrugs thereof, solvates thereof, and all stereoisomers thereof.
Specific examples include compounds having the following structures:
